Bibliographic details of the publications referred to by both author and numerically in this specification are collected at the end of the description.
The reference to any prior art in this specification is not, and should not be taken as, an acknowledgment or any form of suggestion that that prior art forms part of the common general knowledge in Australia.
The LIM domain defines a conserved cysteine-rich structure comprising two tandemly repeated zinc fingers and is found in a large group of diverse proteins (reviewed in 1, 2). This motif, originally identified in LIM-homeodomain transcription factors, may either occur alone (as one or more copies) or in association with heterologous domains such as a protein kinase or homeobox domain. Targeted gene disruption has established that. LIM domain-containing proteins have critical functions in cell-fate specification and differentiation (3).
The LMO family consists of four members (designated LM01-4), each of which comprises two tandem LIM domains. LM02 is essential for embryonic hematopoiesis and is thought to function at the level of the pluripotent stem cell (11). Little is known about the function of LM03, discovered on the basis of sequence homology. The most recently described member, LM04, was isolated by virtue of its interaction with Ldb1/NL1/CLIM and in an expression screen with autologous serum (12-15). Ldb1 is a multifunctional adaptor protein that interacts with LMO proteins and other nuclear LIM-containing factors (16-19). The LM04 gene is widely expressed in both embryonic and adult tissues (12, 13, 15). Like the other members of this family, it is presumed that LM04 is a transcriptional cofactor that primarily functions as a docking site for other factors. LM04 may also contribute an activation or repression domain to influence transcriptional activity.
In work leading up to the present invention the inventors have determined that LM04 plays a role in mammary development and in breast oncogenesis. The LM04 gene is developmentally regulated in mammary epithelium and LM04 together with Ldb1 have been found to act as negative regulators of mammary epithelial differentiation. Significantly, overexpression of the LM04 gene was found in greater than 50% of primary breast cancers, indicating that this protein contributes to the pathogenesis of breast cancer.